Fatigue is a common clinical manifestation of infectious and autoimmune diseases; it is also the chief complaint of patients with chronic fatigue syndrome (CFS). Cytokines, which are produced during immune activation, have been hypothesized to affect brain cell function resulting in fatigue. The work proposed, which is potentially relevant to und erstanding CFS, will test the cytokine hypothesis of immunologically mediated chronic fatigue using recently developed murine models of whole cell Corynebacterium parvum antigen inoculation. The specific aims of this research proposal are to: (1) characterize a murine model of immunologically mediated chronic fatigue (Specific Aim 1); (2) evaluate the association between selected cytokine expression in splenic and brain tissues of mice and chronic fatigue development (Specific Aim 2); and (3) investigate the effects of drugs known to inhibit cytokine production on immunologically mediated chronic fatigue (Specific Aim 3). For these studies, fatigue will be quantified by measuring the degree and duration of reduction in spontaneous daily running activity on an exercise wheel following whole cell C. parvum antigen inoculation in C57BL/6 female mice. Serum cytokine levels (interleukin [IL]-1, IL-6, transforming growth factor-beta, interferon-alpha, and tumor necrosis factor-alpha) and cytokine mRNA expression in splenic and brain tissues of inoculated mice will be correlated with the development of chronic fatigue. Treatment of mice which display immunologically mediated chronic fatigue with drugs known to inhibit cytokine expression will be performed to assess their impact on development of chronic fatigue and their therapeutic potential in disorders involving immunologically mediated fatigue. These studies will enhance our understanding of the pathophysiology of immunologically mediated fatigue and will foster the development of new treatment strategies, particularly for patients with CFS.